Abstract
BackgroundSplit hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). 17p13.3 duplications containing BHLHA9 are associated with SHFLD. Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. The severity of long bone defect could not be simply explained by BHLHA9 overdosage or 17p13.3 duplication.MethodsA four-generation Chinese SHFM family was recruited. Three family members have long bone defects, one male was severely affected with hypoplasia or aplasia in three of four limbs. Linkage analysis and direct sequencing of candidate genes were used to exclude six responsible genes/loci for isolated SHFM. Array comparative genomic hybridization (CGH) was performed to detect copy number variations on a genome-wide scale, and quantitative real-time polymerase chain reaction (qPCR) assays were designed to validate the identified copy number variation in the index and other family members.ResultsNo mutations were found in genes or loci linked to isolated SHFM. A ~ 966 kb duplication was identified in 17p13.3 by array CGH, in which BHLHA9 surrounding region presented as triplication. The qPCR assays confirmed the indicated 17p13.3 duplication as well as BHLHA9 triplication in all available affected family members and other two asymptomatic carriers. Given the incomplete penetrance in SHFLD, those two carriers were regarded as non-penetrant, which suggested that the genomic rearrangement was co-segregated with malformation in this family.ConclusionsThe present study reports an additional SHFLD family case with 17p13.3 genomic rearrangement. To our knowledge, the 966 kb genomic rearrangement is larger in size than any previously reported SHFLD-associated 17p13.3 duplication, and the present family shows marked phenotypic variability with two asymptomatic carriers and one patient with an extremely severe phenotype. This rare case provides the opportunity to identify underlying genotype-phenotype correlations between SHFLD and 17p13.3 genomic rearrangement.
Highlights
Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity
Non-syndromic SHFM includes isolated SHFM; and SHFM in association with other limb manifestations, such as tibia or femur aplasia, is called SHFM with long bone deficiency (SHFLD), and others involving fibula defects are designated as fibular agenesis with ectrodactyly (OMIM 113310)
Patient III6 is phenotypically normal, and has obtained four abortions, all because of limb malformations detected in the fetus by ultrasound, Table 1 Limb features of family members
Summary
Split hand/foot malformation (SHFM) is a genetically heterogeneous limb malformation with variable expressivity. SHFM with tibia or femur aplasia is called SHFM with long bone deficiency (SHFLD). Cases with variable SHFLD phenotype and different 17p13.3 duplicated regions are reported. Non-syndromic SHFM includes isolated SHFM; and SHFM in association with other limb manifestations, such as tibia or femur aplasia, is called SHFM with long bone deficiency (SHFLD), and others involving fibula defects are designated as fibular agenesis with ectrodactyly (OMIM 113310). Six genes/loci (SHFM1–6) have been identified as responsible for isolated SHFM. These include deletions, duplications, or rearrangements on 7q21.2-q21.3, heterozygous/homozygous mutations in DLX5 or heterozygous mutations in DLX6 (SHFM1, OMIM 183600), heterozygous duplications on 10q24 (SHFM3, OMIM 246560), heterozygous mutations in TP63 (SHFM4, OMIM 605289), heterozygous deletions on 2q31 (SHFM5, OMIM 606708) and biallelic mutations in WNT10B (SHFM6, OMIM 225300); in addition, SHFM2 has been mapped to Xq26.3 by linkage analysis. Dominant TP63 mutations can result in ectrodactyly, ectodermal dysplasia, and cleft lip/ palate syndrome 3 (EEC3, OMIM 604292)
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